Yount E A, Felten S Y, O'Connor B L, Peterson R G, Powell R S, Yum M N, Harris R A
J Pharmacol Exp Ther. 1982 Aug;222(2):501-8.
The metabolic and toxic effects of 2-chloropropionate and dichloroacetate, activators of the pyruvate dehydrogenase complex, were compared. In 4-hr fasted mice, the oral LD50 values for 2-chloropropionate and dichloroacetate were 15.4 +/- 0.1 and 32.1 +/- 1.1 mmol/kg, respectively. In suckling rats, both compounds effectively lowered blood lactate and glucose levels and increased blood ketone bodies. Although comparable effects were brought about by both compounds on other metabolites, dichloroacetate caused a greater increase in blood ketone bodies. In a prolonged oral toxicity study using male rats, both compounds decreased growth rate and food consumption and caused neurotoxic effects. Both compounds brought about hind limb weakness, slower nerve conduction velocities and decreased diameter of tibial nerves. 2-Chloropropionate treatment caused testicular abnormalities manifested by testicular maturation arrest and degeneration of germ cells. 2-Chloropropionate-treated rats had significantly lower plasma triacylglycerol levels than control or dichloroacetate-treated rats. In mature rats, total serum ketone bodies were increased by dichloroacetate but not significantly elevated by 2-chloropropionate. Although 2-chloropropionate may lack sufficient safety to warrant chronic use in humans, it is a useful research tool for studying the metabolic effects of activation of the pyruvate dehydrogenase complex. Since 2-chloropropionate is not converted to oxalate and is not as ketogenic as dichloroacetate, 2-chloropropionate may be useful clinically in situations requiring only short-term therapy.
比较了丙酮酸脱氢酶复合体激活剂2-氯丙酸酯和二氯乙酸的代谢及毒性作用。在禁食4小时的小鼠中，2-氯丙酸酯和二氯乙酸的经口半数致死剂量（LD50）值分别为15.4±0.1和32.1±1.1 mmol/kg。在乳鼠中，这两种化合物均能有效降低血乳酸和血糖水平，并增加血酮体。尽管两种化合物对其他代谢物产生了类似的作用，但二氯乙酸使血酮体增加得更多。在一项使用雄性大鼠的长期经口毒性研究中，这两种化合物均降低了生长速率和食物摄入量，并产生了神经毒性作用。两种化合物均导致后肢无力、神经传导速度减慢以及胫神经直径减小。2-氯丙酸酯处理导致睾丸异常，表现为睾丸成熟停滞和生殖细胞退化。经2-氯丙酸酯处理的大鼠血浆三酰甘油水平显著低于对照组或经二氯乙酸处理的大鼠。在成年大鼠中，二氯乙酸使血清总酮体增加，但2-氯丙酸酯未使其显著升高。尽管2-氯丙酸酯可能缺乏足够的安全性以保证在人体中长期使用，但它是研究丙酮酸脱氢酶复合体激活的代谢效应的有用研究工具。由于2-氯丙酸酯不会转化为草酸盐，且生酮作用不如二氯乙酸，因此2-氯丙酸酯在仅需要短期治疗的情况下可能具有临床应用价值。
